Hepatitis C Virus (HCV) infects approximately 4 million Americans and 170 million people on a worldwide basis. Despite substantial reductions in blood product-related transmission over the past two decades, especially in resourced settings, transmission among injecting drug users continues and there is increasing evidence of transmission among individuals engaged in higher risk sexual behaviors. Furthermore, since most morbidity from the virus is related to chronic liver disease and requires 20 or more years to develop, HCV-related morbidity and mortality is projected to increase in the US for at least the next decade regardless of the current transmission rate. Over the last 10 years there have been steady improvements in therapeutic options with the evolution of pegylated interferon (PEG-Ifn)-ribavirin based treatment regimens. Despite these advances, only about 50% of those with the HCV genotype most common in the US (Genotype 1) who can tolerate a full course of therapy respond fully to PEG-Ifn based therapy. Contraindications and toxicities to components of the current regimen preclude many treatment candidates from initiating or completing a full course of therapy and suggest that substantial further improvement in Ifn-based therapies is unlikely. Over the past 3 years there has been increasing progress in the development of small molecular inhibitors of the HCV NS3/NS4a protease and the NS5b polymerase. Compounds directed at each molecular target have clearly demonstrated proof-of-concept in vivo and combination studies with PEG-Ifn are underway. HCV shares two critical properties with HIV: high replication rates and low replicative fidelity, that make it highly likely that efficacious all small molecular regimens will require the use of multiple agents directed at several molecular targets. As is outlined in this application, two research groups are collaborating to optimize a series of orally active nucleoside phosphonate compounds directed at the HCV polymerase. We have created a series of alkoxyalkyl nucleoside phosphonate derivatives that substantially enhance both the antiviral activity and the pharmacokinetic properties of parent nucleosides. Using an approach that we have successfully employed in drug discovery directed at HIV, poxviruses and herpes viruses we propose to systematically evaluate this approach in the setting of HCV infection with the view that the next substantial advance in HCV therapeutics will likely require the development of interferon-free regimens and that this will require the availability of a much larger array of small molecular HCV inhibitors than is currently in hand.